1. Field Of The Invention
The present invention relates to unsymmetrical dithiol ketals composed of a farnesyl mercaptan unit and a thiol phenol moiety. The compounds of the present invention are useful in the treatment or prevention of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
2. Description of the Prior Art
Unsymmetrical dithiol ketals composed of a farnesyl mercaptan unit and a thiol phenol moiety are unknown in the literature. However, examples of similar symmetrical diaryl dithiol ketals are abundant. (Newworth and Laufer, J. Med. Chem, 170, 13(4), 722).
An example of a known symmetrical diaryl dithiol ketal is Probucol (4,4'-(isopropyledevedithio)bis(2,6-di-tertbutylphenol). Probucol is a potent synthetic hypolipidemic agent effective in human at dosage around 500 mg b.i.d. The mechanism of action of this symmetrical diaryl dithiol ketal has been a subject of debate for many years. It has recently been suggested that the antioxidation properties of Probucol is responsible for its therapeutic actions. (Minakami et. al., Drug Res. 1989, 39(II), 1090). Dithiol ketals are hydrolysed to give reductive intermediates which are capable of neutralizing any harmful oxidative products such as hydroxyl radical. The precise mechanism of how the reductive species are released is still unclear as is the interaction with the oxidizing toxic substances. Being a highly lipophilic compound, Probucol (or any other non-polar substance) is transported into plasma in lipoproteins, primarily in LDL and VLDL (Marshall, F. N., Artery, 1982, 10, 7), and is preferentially distributed in high concentrations in cell membranes which consist of phospholipids. Thus, it is strategically positioned to offer maximum protective action against oxidative modifications to the lipoproteins and cell membranes.
The unsymmetrical dithiol ketals of the present invention act not only as antioxidants, but also as potential biofeedback regulators. The unsymmetrical dithiol ketals of the present invention are also capable of down regulating the crucial hydroxymethylglutaryl coenzyme A reductase (HMGCo-A reductase) and, therefore, are more desirable for the treatment of hypolipidemia.